CN109574868B - Preparation method of tetracycline and epimer deuterated internal standard substance thereof - Google Patents

Preparation method of tetracycline and epimer deuterated internal standard substance thereof Download PDF

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CN109574868B
CN109574868B CN201811627427.9A CN201811627427A CN109574868B CN 109574868 B CN109574868 B CN 109574868B CN 201811627427 A CN201811627427 A CN 201811627427A CN 109574868 B CN109574868 B CN 109574868B
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deuterated
tetracycline
internal standard
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张磊
郝明锋
韩世磊
徐浩
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Tianjin Alta Scientific Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/16—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of hydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
    • C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Abstract

The invention provides a method for preparing tetracycline and an epimer deuterated internal standard substance thereof, which comprises the steps of cyclization, ring opening and reduction to obtain a demethylated primary amine intermediate, and finally, carrying out reductive amination on deuterated paraformaldehyde to obtain a tetracycline deuterated internal standard reagent. Compared with the traditional method for preparing the tetracycline internal standard reagent labeled by the stable isotope through fermentation or total synthesis, the method disclosed by the invention has the advantages of short steps, simplicity and convenience in operation, high yield, low cost, good quality and the like. The purity and the atomic deuteration rate of the obtained product are both more than 98 percent.

Description

Preparation method of tetracycline and epimer deuterated internal standard substance thereof
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of deuterated stable isotope internal standard reagents of aureomycin, tetracycline, terramycin, epimers thereof and the like in tetracycline antibiotics.
Background
The tetracycline antibiotics are a broad-spectrum antibiotics produced by actinomycetes, and include aureomycin, oxytetracycline, tetracycline and semisynthetic derivatives of methacycline, doxycycline and dimethylamino tetracycline, and all have the structure containing tetracene basic skeleton. Is widely used for various bacteria and infections caused by rickettsia, chlamydia, mycoplasma and the like. Tetracycline antibiotics are a broad-spectrum antibiotic commonly used by veterinarians, are widely used for preventing and treating animal diseases, and are often used as animal growth promoters. However, the medicine has great toxic and side effects on the stomach, intestine, liver and teeth of human body while playing the medicine effect, and in addition, the medicine can cause superinfection, anaphylactic reaction and teratogenesis. At present, the phenomenon of abuse of antibiotics exists in the animal breeding process, so that the residual contamination of the antibiotics in animal food is caused, the physical health of consumers is directly influenced, and the drug resistance of bacteria is increased.
In conclusion, the method has very important significance for detecting the tetracycline antibiotic residue in the field of food detection, and the stable isotope labeled compound has the advantages of simple pretreatment, good repeatability, low detection limit and the like in the process of carrying out food safety monitoring and detection by utilizing high-resolution mass spectrometry. The prior art for producing the tetracycline stable isotope internal standard reagent has long production route, complex operation process and high cost, which seriously restrict the application of the tetracycline stable isotope internal standard reagent. Therefore, the method for researching and developing the tetracycline internal standard substance has the advantages of short technical route, simple and convenient operation, high yield, low cost and good quality, and has important economic value and social significance.
Disclosure of Invention
The invention aims to provide a preparation method of tetracycline and an epimer deuterated internal standard substance thereof, which has the advantages of reasonable design, cheap and easily-obtained raw materials, short technical route, simple and convenient operation, high yield and low cost. The technical scheme adopted by the invention mainly comprises the following steps:
(one) cyclization reaction to prepare intermediate II
Dissolving a tetracycline compound in a mixed solvent of water and concentrated hydrochloric acid, adding N-chlorosuccinimide in batches under stirring at room temperature, and stirring to react to obtain an intermediate II after the addition is finished;
hydrazine (di) hydrate hydrazinolysis ring to obtain intermediate III
And (3) dissolving the intermediate II prepared in the step (I) in ethanol, dropwise adding an ethanol solution in which hydrazine hydrate is dissolved at room temperature, and stirring at room temperature to react after the addition is finished to obtain an intermediate III.
(III) reduction to obtain an intermediate IV
Dissolving the intermediate III prepared in the step (II) in a mixed solution of acetone and water, adding sodium hydrosulfite in batches at room temperature, and stirring to react after adding to obtain an intermediate IV;
(IV) reductive amination to give the end products V and VI
Dissolving the intermediate IV prepared in the step (three) in a mixed solution of methanol and acetic acid, adding deuterated paraformaldehyde, adding deuterated sodium cyanoborohydride in batches at room temperature, and stirring to react overnight after the addition is finished to obtain final products V and VI;
the reaction route is as follows:
Figure GDA0003286667230000021
further, 1.2 equivalents of concentrated hydrochloric acid and 2.4 equivalents of N-chlorosuccinimide are required to be added in the step (one), and the N-chlorosuccinimide is stirred and reacts for 30min after the addition of the N-chlorosuccinimide is finished; the temperature was 25 ℃.
In the step (one), acid which needs to be added can be strong protonic acid such as hydrobromic acid, concentrated sulfuric acid and the like, and N-chlorosuccinimide can also be N-bromosuccinimide.
In the step (II), hydrazine hydrate is used in 1 time equivalent. Reacting at 25 ℃ for 18 h.
In the step (III), the sodium hydrosulfite accounts for 5 equivalents. The reaction was carried out at 25 ℃ for 30 min.
In the step (III), the sodium hydrosulfite reducing agent can also be iron powder, zinc powder, sodium nitrite, stannous chloride and other reducing agents, and the solvent can be methanol, ethanol and other reagents.
In the step (IV), about 20 times of equivalent of acetic acid is required to be added as a catalyst, so that the reaction is favorably carried out more, and the reaction is converted into the tetracycline D6 compound rather than the poorly-converted tetracycline D6 compound. The reaction is carried out for 15h at 25 ℃.
The reducing agent in the step (IV) can also be a reducing agent such as sodium boron deuteride, potassium boron deuteride, sodium boron deuteride acetate and the like, and the solvent can be dichloromethane, 1, 2-dichloroethane, ethanol and the like.
In the step (IV), the tetracycline deuterated internal standard substance can be obtained by adding acid for catalysis, or the epimeddium tetracycline deuterated internal standard reagent can be mainly obtained without adding acid for catalysis.
The method has the beneficial effects that: the method has short technical route, uses a large amount of water as a solvent for reaction, and greatly reduces the dosage of the organic solvent. The method introduces the deuterated functional group in the last step of the preparation, thereby not only reducing the preparation risk, but also ensuring the abundance of isotopes.
Detailed Description
The invention will be described in detail with reference to specific embodiments.
Example 1
Preparation of (1R,4aS,11R,11aS,12aR) -1,2,4a,5, 7-pentahydroxy-11-methyl-4, 6-dioxomethylene-1, 4,4a,6,11,11a,12,12 a-octahydro-1, 11-epoxytetracene-3-carboxamide (IIa):
dissolving 4.6 g of tetracycline (Ia) in 250 ml of aqueous solution containing 1 ml of concentrated hydrochloric acid, adding 3.5 g of N-chlorosuccinimide in batches at 25 ℃, and stirring and reacting for 30min at 25 ℃ after the addition is finished; suction filtration was carried out, the filter cake was washed with water, the filter cake was dissolved in 300 ml of methyl tert-butyl ether and washed 4 times with 50 ml of water. The solvent was dried by rotary evaporation under reduced pressure to give the product 3.2g of a pale yellow solid which was used directly in the next reaction in 74.4% yield. LCMS (ESI +): 416[ M + H ] M/z]+。
Example 2
Preparation of (4aS,5aS,6S,12aS, E) -4-hydrazino-3, 6,10,12,12 a-pentahydroxy-6-methyl-1, 11-dioxomethylene-1, 4,4a,5,5a,6,11,12 a-octahydro-2-carboxamide (IIIa):
3.2g of (1R,4aS,11R,11aS,12aR) -1,2,4a,5, 7-pentahydroxy-11-methyl-4, 6-dioxomethylene-1, 4,4a,6,11,11a,12,12 a-octahydro-1, 11-epoxytetracene-3-carboxamide (IIa) are dissolved in 25 ml of a 95% ethanol solution, and a 25 ml ethanol solution containing 0.46 ml of 80% hydrazine hydrate is slowly added dropwise to the reaction mixture at 25 ℃. After dropping, the reaction is carried out for 18h under the condition of heat preservation. The solvent was dried by spinning to give 3.3 g of a reddish brown solid which was used directly in the next reaction. The yield was 99.7%. LCMS (ESI +): 430[ M + H ] M/z]+。
Example 3
Preparation of (4aS,5aS,6S,12aS) -4-amino-3, 6,10,12,12 a-pentahydroxy-6-methyl-1, 11-dioxomethylene-1, 4,4a,5,5a,6,11,12 a-octahydro-2-carboxamide (IVa):
3.3 g of (4aS,5aS,6S,12aS, E) -4-hydrazino-3, 6,10,12,12 a-pentahydroxy-6-methyl-1, 11-dioxomethylene-1, 4,4a,5,5a,6,11,12 a-octahydro-2-carboxamide (IIIa) are dissolved in 130 ml of a mixed solution of acetone and 100% of water, 6.6 g of sodium dithionite are added in portions at 25 ℃, the temperature is controlled to be about 30 ℃,after the addition, the reaction was stirred at 25 ℃ for 30 min. After the reaction was completed, 3 g of activated carbon was added, and after stirring for 10 minutes, celite was added, suction-filtered, and washed with a mixed solution of water and acetone 1/1. Mixing the filtrates, spin-drying acetone, adjusting pH to 4-5, washing water layer with ethyl acetate, extracting with n-butanol, drying with anhydrous sodium sulfate, vacuum filtering, and spin-drying to obtain 1.3 g of crude product. The crude product was dissolved in 50 ml of N, N-dimethylformamide, and 18 ml of water were added dropwise at room temperature and stirred for 2 hours. Reddish brown solid is separated out, and 0.9 g of pure product is obtained by suction filtration. The yield was 28.1%. LCMS (ESI +): 417[ M + H ] M/z]+。
Example 4
Preparation of tetracycline and its epimer D6(Va, VIa):
100 mg of (4aS,5aS,6S,12aS) -4-amino-3, 6,10,12,12 a-pentahydroxy-6-methyl-1, 11-dioxomethylene-1, 4,4a,5,5a,6,11,12 a-octahydro-2-carboxamide (IVa) was dissolved in 10 ml of anhydrous methanol, 0.25 ml of acetic acid, 36 mg of deuterated paraformaldehyde and 50 mg of sodium cyanoboroboron deuteride were added, and the reaction was carried out at 25 ℃ for 15 hours under nitrogen protection. After the reaction was complete, purification by preparative HPLC gave 30 mg of tetracycline D6 and 20 mg of anhydrotetracycline D6, respectively, as a yellowish solid. The total yield is 46.3%. LCMS (ESI +): 451[ M + H ] M/z]+,Va：1H NMR(400MHz,MeOD)δ7.81(d,J＝8.0Hz,1H)，7.62(m,1H),6.78(d,J＝8.6Hz,1H),3.49(s,1H),3.35(s,1H),3.24-3.28(m,1H)2.85-2.90(m,1H),2.73(s,3H).VIa：1H NMR(400MHz,MeOD)δ7.81(d,J＝8.0Hz,1H)，7.62(m,1H),6.78(d,J＝8.6Hz,1H),3.47(d,J＝9.1Hz1H),3.23(s,1H),3.24-3.28(m,1H)2.81-2.89(m,1H),2.73(s,3H).
The above description is for the purpose of describing particular embodiments of the present invention, but the present invention is not limited to the particular embodiments described herein. All equivalent changes and modifications made within the scope of the invention shall fall within the scope of the patent coverage of the invention.

Claims (6)

1. A preparation method of tetracycline and epimer deuterated internal standard substance is characterized in that,
the method mainly comprises the following steps:
(one) cyclization reaction to prepare intermediate II
Dissolving a tetracycline compound in a mixed solvent of water and strong protonic acid, adding N-halogenated succinimide in batches under stirring at room temperature, and reacting under stirring to obtain an intermediate II;
hydrazine (di) hydrate hydrazinolysis ring to obtain intermediate III
Dissolving the intermediate II prepared in the step (one) in ethanol, dropwise adding an ethanol solution in which hydrazine hydrate is dissolved at room temperature, and stirring at room temperature to react after adding to obtain an intermediate III;
(III) reduction to obtain an intermediate IV
Dissolving the intermediate III prepared in the step (II) in a solvent X, adding a reducing agent X in batches at room temperature, and stirring to react after the addition to obtain an intermediate IV;
(IV) reductive amination to give the end products V and VI
Dissolving the intermediate IV prepared in the step (III) in a solvent Y, adding deuterated paraformaldehyde, adding a reducing agent Y in batches at room temperature, and stirring to react overnight after the addition to obtain final products V and VI;
in the step (IV), adding 20 times of equivalent of acid catalyst, wherein the acid catalyst is acetic acid; reacting for 15 hours at 25 ℃;
the reducing agent Y in the step (IV) is deuterated cyano sodium borohydride, boron sodium deuteride, boron potassium deuteride or boron sodium deuteride acetate, and the solvent Y is methanol, dichloromethane, 1, 2-dichloroethane or ethanol;
the reaction route is as follows:
Figure FDA0003286667220000011
2. the method for preparing tetracyclines and their epimeric deuterated internal standard substances according to claim 1, wherein 1.2 equivalents of strong protonic acid and 2.4 equivalents of N-halogenated succinimide are added in the step (one), and the N-halogenated succinimide is stirred and reacted for 30min at 25 ℃ after the addition is finished.
3. The method for preparing tetracyclines and epimer deuterated internal standards thereof according to claim 2, wherein in step (a) the strong protic acid is concentrated hydrochloric acid, hydrobromic acid or concentrated sulfuric acid, and the N-halogenated succinimide is N-chlorosuccinimide or N-bromosuccinimide.
4. The method for preparing tetracyclines and epimer deuterated internal standard thereof according to claim 2, wherein in the step (two), hydrazine hydrate is used in 1-fold equivalent; reacting at 25 ℃ for 18 h.
5. The method for preparing tetracyclines and their epimeric deuterated internal standards according to claim 2, wherein in step (three), the reducing agent X is 5 equivalents; the reaction was carried out at 25 ℃ for 30 min.
6. The method for preparing tetracyclines and their epimeric deuterated internal standard substances according to claim 2, wherein in step (III), the reducing agent X is sodium hydrosulfite, iron powder, zinc powder, sodium nitrite or stannous chloride, and the solvent X is a mixed solution of acetone and water, methanol or ethanol.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US3824285A (en) * 1967-09-13 1974-07-16 Pfizer 4-oxo-4-dedimethylaminotetracycline-4,6-hemiketals
CN1811454A (en) * 2006-01-19 2006-08-02 镇江出入境检验检疫局检验检疫综合技术中心 Cyclomycin family antibiotic enzyme-linked immunoassay reagent kit
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US20130296279A1 (en) * 2010-11-11 2013-11-07 Concert Pharmaceutcals Inc. Substituted tetracyclines

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US3622627A (en) * 1967-09-13 1971-11-23 Pfizer 4-dedimethylaminatetracycline and 5a, 6-anhydro derivatives thereof
US3824285A (en) * 1967-09-13 1974-07-16 Pfizer 4-oxo-4-dedimethylaminotetracycline-4,6-hemiketals
CN1811454A (en) * 2006-01-19 2006-08-02 镇江出入境检验检疫局检验检疫综合技术中心 Cyclomycin family antibiotic enzyme-linked immunoassay reagent kit
US20100305072A1 (en) * 2006-12-21 2010-12-02 Kim Oak K Substituted Tetracycline Compounds
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Denomination of invention: Preparation of a deuterium internal standard of tetracyclines and their epimers

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